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Title: Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3
Authors: Kasai, Yosuke
Toriguchi, Kan
Hatano, Etsuro
Nishi, Kiyoto
Ohno, Mikiko
Yoh, Tomoaki
Fukuyama, Keita
Nishio, Takahiro
Okuno, Masayuki
Iwaisako, Keiko
Seo, Satoru  kyouindb  KAKEN_id
Taura, Kojiro  kyouindb  KAKEN_id
Kurokawa, Masato
Kunichika, Makoto
Uemoto, Shinji  kyouindb  KAKEN_id
Nishi, Eiichiro
Author's alias: 笠井, 洋祐
波多野, 悦朗
西, 清人
大野, 美紀子
福山, 啓太
西尾, 太宏
楊, 知明
奥野, 将之
祝迫, 惠子
瀬尾, 智
田浦, 康二朗
上本, 伸二
西, 英一郎
Keywords: Hepatocellular carcinoma
prognostic marker
signal transducer and activator of transcription 3
Issue Date: May-2017
Publisher: Wiley-Blackwell
Journal title: Cancer Science
Volume: 108
Issue: 5
Start page: 910
End page: 917
Abstract: Nardilysin (NRDC) is a metalloendopeptidase of the M16 family. We previously showed that NRDC activates inflammatory cytokine signaling, including interleukin-6-signal transducer and activator of transcription 3 (STAT3) signaling. NRDC has been implicated in the promotion of breast, gastric and esophageal cancer, as well as the development of liver fibrosis. In this study, we investigated the role of NRDC in the promotion of hepatocellular carcinoma (HCC), both clinically and experimentally. We found that NRDC expression was upregulated threefold in HCC tissue compared to the adjacent non-tumor liver tissue, which was confirmed by immunohistochemistry and western blotting. We also found that high serum NRDC was associated with large tumor size (>3 cm, P = 0.016) and poor prognosis after hepatectomy (median survival time 32.0 vs 73.9 months, P = 0.003) in patients with hepatitis C (n = 120). Diethylnitrosamine-induced hepatocarcinogenesis was suppressed in heterozygous NRDC-deficient mice compared to their wild-type littermates. Gene silencing of NRDC with miRNA diminished the growth of Huh-7 and Hep3B spheroids in vitro. Notably, phosphorylation of STAT3 was decreased in NRDC-depleted Huh-7 spheroids compared to control spheroids. The effect of a STAT3 inhibitor (S3I-201) on the growth of Huh-7 spheroids was reduced in NRDC-depleted cells relative to controls. Our results show that NRDC is a promising prognostic marker for HCC in patients with hepatitis C, and that NRDC promotes tumor growth through activation of STAT3.
Rights: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
DOI(Published Version): 10.1111/cas.13204
PubMed ID: 28207963
Appears in Collections:Journal Articles

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